Tumor-associated macrophage-derived itaconic acid contributes to nasopharyngeal carcinoma progression by promoting immune escape via TET2.

Nasopharyngeal carcinoma (NPC) is a malignant tumor of epithelial origin in head and neck with high incidence rate in South China, Southeast Asia and North Africa. The intervention of tumor-associated macrophages (Mφs) (TAMs)-mediated immunosuppression is a potential therapeutic strategy against tumor metastasis, but the exact mechanisms of TAM-mediated immunosuppression in nasopharyngeal carcinoma are unclear. Furthermore, how TAM affects the occurrence and development of nasopharyngeal carcinoma through metabolism is rarely involved. In this work, we revealed that NPC cells promoted M2-type Mφ polarization and elevated itaconic acid (ITA) release. Also, TAMs facilitated NPC cell proliferation, migration, and invasion through immune response gene 1 (IRG1)-catalyzed ITA production. Then, IRG1-mediated ITA production in TAMs repressed the killing of CD8+ T cells, induced M2-type polarization of TAMs, and reduced the phagocytosis of TAMs. Moreover, we demonstrated ITA played a tumor immunosuppressive role by binding and dampening ten-eleven translocation-2 (TET2) expression. Finally, we proved that ITA promotes NPC growth by facilitating immune escape in CD34+ hematopoietic stem cell humanized mice. In Conclusion, TAM-derived ITA facilitated NPC progression by enhancing immune escape through targeting TET2, highlighting that interfering with the metabolic pathway of ITA may be a potential strategy for NPC treatment.

13,14-seco withaphysalins from Physalis minima and their inhibitory effects on NLRP3 inflammasome activation.

Seven new 13,14-seco withaphysalins including two new skeletons (1 and 9) were isolated from the whole plants of Physalis minima, together with three known analogues (6-8). Among them, compound 1 was an extremely rare steroid with a 6, 8-cyclo ring. Their structures were established by extensive analysis of spectroscopic data, experimental electronic circular dichroism measurements, and single-crystal X-ray crystallographic analysis. In Raw264.7 cells, compounds 1-3, 5, 6, and 8 demonstrated potent ability to reduce the NLRP3-dependent caspase-1 activation. Among these compounds, 1 and 2 showed a superior potential, consistently concentration-dependent downregulating NLRP3-dependent proinflammatory cytokine IL-1ß production in macrophage. Mechanistically, compounds 1 and 2 reduced the cleavage of caspase-1 and GSDMD, and exhibited no obvious impact both on the NF-κB activation and the expression of NLRP3 and IL-1ß, suggesting that the compounds target the activation of the NLRP3 pathway mainly by inhibiting the NLRP3 inflammasome activation step rather than the priming step.

Prenatal dexamethasone exposure impairs rat blood-testis barrier function and sperm quality in adult offspring via GR/KDM1B/FSTL3/TGFß signaling.

Both epidemiological and animal studies suggest that adverse environment during pregnancy can change the offspring development programming, but it is difficult to achieve prenatal early warning. In this study we investigated the impact of prenatal dexamethasone exposure (PDE) on sperm quality and function of blood-testis barrier (BTB) in adult offspring and the underlying mechanisms. Pregnant rats were injected with dexamethasone (0.1, 0.2 and 0.4 mg·kg-1·d-1, s.c.) from GD9 to GD20. After weaning (PW4), the pups were fed with lab chow. At PW12 and PW28, the male offspring were euthanized to collect blood and testes samples. We showed that PDE significantly decreased sperm quality (including quantity and motility) in male offspring, which was associated with impaired BTB and decreased CX43/E-cadherin expression in the testis. We demonstrated that PDE induced morphological abnormalities of fetal testicle and Sertoli cell development originated from intrauterine. By tracing to fetal testicular Sertoli cells, we found that PDE dose-dependently increased expression of histone lysine demethylases (KDM1B), decreasing histone 3 lysine 9 dimethylation (H3K9me2) levels of follistatin-like-3 (FSTL3) promoter region and increased FSTL3 expression, and inhibited TGFß signaling and CX43/E-cadherin expression in offspring before and after birth. These results were validated in TM4 Sertoli cells following dexamethasone treatment. Meanwhile, the H3K9me2 levels of FSTL3 promoter in maternal peripheral blood mononuclear cell (PBMC) and placenta were decreased and its expression increased, which was positively correlated with the changes in offspring testis. Based on analysis of human samples, we found that the H3K9me2 levels of FSTL3 promoter in maternal blood PBMC and placenta were positively correlated with fetal blood testosterone levels after prenatal dexamethasone exposure. We conclude that PDE can reduce sperm quality in adult offspring rats, which is related to the damage of testis BTB via epigenetic modification and change of FSTL3 expression in Sertoli cells. The H3K9me2 levels of the FSTL3 promoter and its expression in the maternal blood PBMC can be used as a prenatal warning marker for fetal testicular dysplasia.

Genetic basis of phenotypic convergence in pig terminal sires using pathway-based selection signature detection methods.

The primary purpose of genetic improvement in lean pig breeds is to enhance production performance. Owing to their similar breeding directions, Duroc and Pietrain pigs are ideal models for investigating the phenotypic convergence underlying artificial selection. However, most important economic traits are controlled by a polygenic basis, so traditional strategies for detecting selection signatures may not fully reveal the genetic basis of complex traits. The pathway-based gene network analysis method utilizes each pathway as a unit, overcoming the limitations of traditional strategies for detecting selection signatures by revealing the selection of complex biological processes. Here, we utilized 13 122 398 high-quality SNPs from whole-genome sequencing data of 48 Pietrain pigs, 156 Duroc pigs and 36 European wild boars to detect selective signatures. After calculating FST and iHS scores, we integrated the pathway information and utilized the r/bioconductor graphite and signet packages to construct gene networks, identify subnets and uncover candidate genes underlying selection. Using the traditional strategy, a total of 47 genomic regions exhibiting parallel selection were identified. The enriched genes, including INO80, FZR1, LEPR and FAF1, may be associated with reproduction, fat deposition and skeletal development. Using the pathway-based selection signatures detection method, we identified two significant biological pathways and eight potential candidate genes underlying parallel selection, such as VTN, FN1 and ITGAV. This study presents a novel strategy for investigating the genetic basis of complex traits and elucidating the phenotypic convergence underlying artificial selection, by integrating traditional selection signature methods with pathway-based gene network analysis.

Osteogenic microenvironment affects palatal development through glycolysis.

Palate development involves various events, including proliferation, osteogenic differentiation, and epithelial-mesenchymal transition. Disruption of these processes can result in the cleft palate (CP). Mouse embryonic palatal mesenchyme (MEPM) cells are commonly used to explore the mechanism of palatal development and CP. However, the role of the microenvironment in the biological properties of MEPM cells, which undergoes dynamic changes during palate development, is rarely reported. In this study, we investigated whether there were differences between the palatal shelf mesenchyme at different developmental stages. Our results found that the palatal shelves facilitate proliferation at the early palate stage at mouse embryonic day (E) 13.5 and the tendency towards osteogenesis at E15.5, the late palate development stage. And the osteogenic microenvironment, which was mimicked by osteogenic differentiation medium (OIM), affected the biological properties of MEPM cells when compared to the routine medium. Specifically, MEPM cells showed slower proliferation, shorter S phase, increased apoptosis, and less migration distance after osteogenesis. E15.5 MEPM cells were more sensitive than E13.5, showing an earlier change. Moreover, E13.5 MEPM cells had weaker osteogenic ability than E15.5, and both MEPM cells exhibited different Lactate dehydrogenase A (LDHA) and Cytochrome c (CytC) expressions in OIM compared to routine medium, suggesting that glycolysis might be associated with the influence of the osteogenic microenvironment on MEPM cells. By comparing the stemness of the two cells, we investigated that the stemness of E13.5 MEPM cells was stronger than that of E15.5 MEPM cells, and E15.5 MEPM cells were more like differentiated cells than stem cells, as their capacity to differentiate into multiple cell fates was reduced. E13.5 MEPM cells might be the precursor cells of E15.5 MEPM cells. Our results enriched the understanding of the effect of the microenvironment on the biological properties of E13.5 and E15.5 MEPM cells, which should be considered when using MEPM cells as a model for palatal studies in the future.

Benzo[a]pyrene exposure disrupts the organelle distribution and function of mouse oocytes.

Benzo[a]pyrene (BaP) is a polycyclic aromatic hydrocarbon compound that is generated during combustion processes, and is present in various substances such as foods, tobacco smoke, and burning emissions. BaP is extensively acknowledged as a highly carcinogenic substance to induce multiple forms of cancer, such as lung cancer, skin cancer, and stomach cancer. Recently it is shown to adversely affect the reproductive system. Nevertheless, the potential toxicity of BaP on oocyte quality remains unclear. In this study, we established a BaP exposure model via mouse oral gavage and found that BaP exposure resulted in a notable decrease in the ovarian weight, number of GV oocytes in ovarian, and oocyte maturation competence. BaP exposure caused ribosomal dysfunction, characterized by a decrease in the expression of RPS3 and HPG in oocytes. BaP exposure also caused abnormal distribution of the endoplasmic reticulum (ER) and induced ER stress, as indicated by increased expression of GRP78. Besides, the Golgi apparatus exhibited an abnormal localization pattern, which was confirmed by the GM130 localization. Disruption of vesicle transport processes was observed by the abnormal expression and localization of Rab10. Additionally, an enhanced lysosome and LC3 fluorescence intensity indicated the occurrence of protein degradation in oocytes. In summary, our results suggested that BaP exposure disrupted the distribution and functioning of organelles, consequently affecting the developmental competence of mouse oocytes.

Discovery and optimization of 3-(indolin-5-yloxy)pyridin-2-amine derivatives as potent necroptosis inhibitors.

Necroptosis is a form of regulated necrotic cell death and has been confirmed to play pivotal roles in the pathogenesis of multiple autoimmune diseases such as rheumatoid arthritis (RA) and psoriasis. The development of necroptosis inhibitors may offer a promising therapeutic strategy for the treatment of these autoimmune diseases. Herein, starting from the in-house hit compound 1, we systematically performed structural optimization to discover potent necroptosis inhibitors with good pharmacokinetic profiles. The resulting compound 33 was a potent necroptosis inhibitor for both human I2.1 cells (IC50 < 0.2 nM) and murine Hepa1-6 cells (IC50 < 5 nM). Further target identification revealed that compound 33 was an inhibitor of receptor interacting protein kinase 1 (RIPK1) with favorable selectivity. In addition, compound 33 also exhibited favorable pharmacokinetic profiles (T1/2 = 1.32 h, AUC = 1157 ng·h/mL) in Sprague-Dawley rats. Molecular docking and molecular dynamics simulations confirmed that compound 33 could bind to RIPK1 with high affinity. In silico ADMET analysis demonstrated that compound 33 possesses good drug-likeness profiles. Collectively, compound 33 is a promising candidate for antinecroptotic drug discovery.

Integrated "Two-in-One" Strategy for High-Rate Electrocatalytic CO2 Reduction to Formate.

The electrochemical CO2 reduction reaction (ECR) is a promising pathway to producing valuable chemicals and fuels. Despite extensive studies reported, improving CO2 adsorption for local CO2 enrichment or water dissociation to generate sufficient H* is still not enough to achieve industrial-relevant current densities. Herein, we report a "two-in-one" catalyst, defective Bi nanosheets modified by CrOx (Bi-CrOx), to simultaneously promote CO2 adsorption and water dissociation, thereby enhancing the activity and selectivity of ECR to formate. The Bi-CrOx exhibits an excellent Faradic efficiency (≈ 100 %) in a wide potential range from ‒0.4 to ‒0.9 V. In addition, it achieves a remarkable formate partial current density of 687 mA cm‒2 at a moderate potential of ‒0.9 V without iR compensation, the highest value at ‒0.9 V reported so far. Control experiments and theoretical simulations revealed that the defective Bi facilitates CO2 adsorption/activation while the CrOx accounts for enhancing the protonation process via accelerating H2O dissociation. This work presents a pathway to boosting formate production through tuning CO2 and H2O species at the same time.

Laeviganoids A-T, ent-Clerodane-Type Diterpenoids from Croton laevigatus.

Laeviganoids A-T (1-20), 20 new ent-clerodane-type diterpenoids featuring a 2-furanone (1-3) or a furan (4-20) ring, as well as six analogues (21-26), were isolated from the roots of Croton laevigatus. Their structures were determined by spectroscopic data analysis, experimental electronic circular dichroism measurements, and X-ray crystallographic studies. Compounds 4-6, 16, 21-24, and 26 could influence the anti-inflammatory protumoral phenotype of macrophages. Among these compounds, 21 and 26 are the most potent, as evidenced by consistently downregulating the classic anti-inflammatory cytokine IL-10 and upregulating the classic pro-inflammatory cytokine TNF-α on the secretion level in RAW 264.7 cells.

Design, synthesis and biological evaluation of 4-aminoquinoline derivatives as receptor-interacting protein kinase 2 (RIPK2) inhibitors.

Receptor-interacting protein kinase 2 (RIPK2) is an essential protein kinase mediating signal transduction by NOD1 and NOD2, which play an important role in regulating immune signalling. In this study, we designed and synthesised a novel series of 4-aminoquinoline-based derivatives as RIPK2 inhibitors. In vitro, compound 14 exhibited high affinity (IC50 = 5.1 ± 1.6 nM) and excellent selectivity to RIPK2 showing in a dendrogram view of the human kinome phylogenetic tree. Bearing favourable lipophilicity and eligible lipophilic ligand efficiency (LipE), compound 14 was selected to investigate cellular anti-inflammatory effect and was identified as a potent inhibitor to reduce the secretion of MDP-induced TNF-α with a dose-dependent manner. Moreover, compound 14 showed moderate stability in human liver microsome. Given these promising results, compound 14 could serve as a favourable inhibitor of RIPK2 for further physiological and biochemical research so as to be used in therapeutic treatment.

Molecular evaluation of Cryptosporidium spp. in sheep in southern Xinjiang, China.

Cryptosporidium spp. are diarrheagenic intestinal parasites with multiple hosts worldwide. A total of 1252 fresh fecal samples of sheep were collected from 10 large-scale farms in southern Xinjiang. Based on the small subunit ribosomal (SSU rRNA) gene of Cryptosporidium, 100 Cryptosporidium-positive samples (8.0%, 100/1252) were detected by PCR. Nine out of 10 farms were positive for Cryptosporidium, with the highest infection rate being 18.4% (23/125) on farm 9 in Qira. The infection rates of Cryptosporidium in pre-weaned lambs, weaned lambs, fattening sheep, and adult sheep were 20.3% (61/301), 10.3% (34/329), 0.9% (3/327), and 0.7% (2/295), respectively. Three Cryptosporidium species were identified, namely, C. xiaoi (n = 61), C. parvum (n = 22), and C. ubiquitum (n = 17). Of them, C. xiaoi was detected on all positive farms and in different age groups of sheep. The subtypes of C. parvum and C. ubiquitum were identified by PCR at the 60 kDa glycoprotein (gp60) gene. Two C. parvum subtypes were identified: IIdA19G1 (n = 21) and IIdA15G1 (n = 1). One C. ubiquitum subtype was identified with XIIa (n = 17). These results indicated the common transmission and genetic diversity of Cryptosporidium in sheep in southern Xinjiang, and further investigations are needed on the zoonotic potential of C. parvum and C. ubiquitum in this region.

Parental presence during induction of anesthesia in children undergoing tonsillectomy and adenoidectomy.

OBJECTIVE: To investigate the effect of parental presence during induction of anesthesia (PPIA) in relieving preoperative anxiety of children undergoing tonsillectomy and adenoidectomy. METHODS: One hundred and sixty children undergoing tonsillectomy and adenoidectomy were divided into the control group and the trial group. The control group received routine nursing in the operation room, while anesthesia was induced in the trial group children in the presence of their parents as part of the routine nursing. The differences in heart rate and mean dynamic pressure during pre-operative visit and anesthesia induction between the two groups were observed and recorded. The Modified Yale Preoperative Anxiety Scale (m-YPAS) and the Induction Compliance Checklist (ICC) were scored. The anxiety status of the children and their family members in the two groups was scored at different times, and the psychological stress of anesthesiologists during anesthesia induction was scored by a visual analogue scale. The differences in each index between the two groups were compared. Operation time and costs in-hospital were also compared. RESULTS: Compared with the control group, the heart rate and blood pressure scores as well as the ICC in the trial group were lower than those in the control group (P < 0.01). On comparing the scores of m-YPAS between the two groups, we observed that the scores of the children in the trial group were lower than those in the control group before entering the induction room and anesthesia induction (P < 0.01). There was no statistical difference between the scores of the children in the trial group and the control group on the day of operation and on the way to the operating room (P > 0.05). The nursing satisfaction scores of the family members in the trial group were significantly superior to those in the control group (P < 0.01). The scores of the visual analogue scale for psychological pressure of anesthesiologists during anesthesia induction were higher in the trial group than in the control group (P < 0.05). The operation time and costs in study group were both significantly higher than those of control group (P < 0.05). CONCLUSION: PPIA can significantly reduce preoperative anxiety and surgical physiological stress response in children undergoing tonsillectomy and adenoidectomy, and it is worth being encouraged.

Inhibition of Cxcr4 Disrupts Mouse Embryonic Palatal Mesenchymal Cell Migration and Induces Cleft Palate Occurrence.

Many processes take place during embryogenesis, and the development of the palate mainly involves proliferation, migration, osteogenesis, and epithelial-mesenchymal transition. Abnormalities in any of these processes can be the cause of cleft palate (CP). There have been few reports on whether C-X-C motif chemokine receptor 4 (CXCR4), which is involved in embryonic development, participates in these processes. In our study, the knockdown of Cxcr4 inhibited the migration of mouse embryonic palatal mesenchymal (MEPM) cells similarly to the use of its inhibitor plerixafor, and the inhibition of cell migration in the Cxcr4 knockdown group was partially reversed by supplementation with C-X-C motif chemokine ligand 12 (CXCL12). In combination with low-dose retinoic acid (RA), plerixafor increased the incidence of cleft palates in mice by decreasing the expression of Cxcr4 and its downstream migration-regulating gene Rac family small GTPase 1 (RAC1) mediating actin cytoskeleton to affect lamellipodia formation and focal complex assembly and ras homolog family member A (RHOA) regulating the actin cytoskeleton to affect stress fiber formation and focal complex maturation into focal adhesions. Our results indicate that the disruption of cell migration and impaired normal palatal development by inhibition of Cxcr4 expression might be mediated through Rac1 with RhoA. The combination of retinoic acid and plerixafor might increase the incidence of cleft palate, which also provided a rationale to guide the use of the drug during conception.

MicroRNAs in Small Extracellular Vesicles from Amniotic Fluid and Maternal Plasma Associated with Fetal Palate Development in Mice.

Cleft palate (CP) is a common congenital birth defect. Cellular and morphological processes change dynamically during palatogenesis, and any disturbance in this process could result in CP. However, the molecular mechanisms steering this fundamental phase remain unclear. One study suggesting a role for miRNAs in palate development via maternal small extracellular vesicles (SEVs) drew our attention to their potential involvement in palatogenesis. In this study, we used an in vitro model to determine how SEVs derived from amniotic fluid (ASVs) and maternal plasma (MSVs) influence the biological behaviors of mouse embryonic palatal mesenchyme (MEPM) cells and medial edge epithelial (MEE) cells; we also compared time-dependent differential expression (DE) miRNAs in ASVs and MSVs with the DE mRNAs in palate tissue from E13.5 to E15.5 to study the dynamic co-regulation of miRNAs and mRNAs during palatogenesis in vivo. Our results demonstrate that some pivotal biological activities, such as MEPM proliferation, migration, osteogenesis, and MEE apoptosis, might be directed, in part, by stage-specific MSVs and ASVs. We further identified interconnected networks and key miRNAs such as miR-744-5p, miR-323-5p, and miR-3102-5p, offering a roadmap for mechanistic investigations and the identification of early CP biomarkers.

Nitrogen addition stimulates N2O emissions via changes in denitrification community composition in a subtropical nitrogen-rich forest.

Microbially driven nitrification and denitrification play important roles in regulating soil N availability and N2O emissions. However, how the composition of nitrifying and denitrifying prokaryotic communities respond to long-term N additions and regulate soil N2O emissions in subtropical forests remains unclear. Seven years of field experiment which included three N treatments (+0, +50, +150 kg N ha-1 yr-1; CK, LN, HN) was conducted in a subtropical forest. Soil available nutrients, N2O emissions, net N mineralization, denitrification potential and enzyme activities, and the composition and diversity of nitrifying and denitrifying communities were measured. Soil N2O emissions from the LN and HN treatments increased by 42.37% and 243.32%, respectively, as compared to the CK. Nitrogen addition significantly inhibited nitrification (N mineralization) and significantly increased denitrification potentials and enzymes. Nitrification and denitrification abundances (except nirK) were significantly lower in the HN, than CK treatment and were not significantly correlated with N2O emissions. Nitrogen addition significantly increased nirK abundance while maintaining the positive effects of denitrification and N2O emissions to N deposition, challenging the conventional wisdom that long-term N addition reduces N2O emissions by inhibiting microbial growth. Structural equation modeling showed that the composition, diversity, and abundance of nirS- and nirK-type denitrifying prokaryotic communities had direct effects on N2O emissions. Mechanistic investigations have revealed that denitrifier keystone taxa transitioned from N2O-reducing (complete denitrification) to N2O-producing (incomplete denitrification) with increasing N addition, increasing structural complexity and diversity of the denitrifier co-occurrence network. These results significantly advance current understanding of the relationship between denitrifying community composition and N2O emissions, and highlight the importance of incorporating denitrifying community dynamics and soil environmental factors together in models to accurately predict key ecosystem processes under global change.

Assessing the spatial distribution of and inequality in 15-minute PCR test site accessibility in Beijing and Guangzhou, China.

China has been planning to construct SARS-CoV-2 antigen testing sites within a 15-min walk in most major cities to timely identify asymptomatic cases and stop the transmission of COVID-19. However, little is known about the spatial distribution of 15-min accessibility to PCR test sites. In this study, we analyze the spatial distribution of and inequality in 15-min accessibility to PCR test sites in two major Chinese cities (Beijing and Guangzhou) based on the cumulative-opportunity model. The results indicate that the current distribution of 15-min accessibility to PCR test sites is satisfactory when normal commuting is not disrupted. However, disruptions of normal commuting (e.g., due to work-from-home restrictions) can negatively influence 15-min accessibility to PCR test sites and increase its inequality. Our study provides policymakers with up-to-date knowledge about the spatial distribution of 15-min accessibility to PCR test sites, identifies the disadvantaged neighborhoods in terms of test site accessibility, and highlights the changes in accessibility and inequality because of travel disruptions.

Endosomal Sorting Complex Required for Transport: The Molecular Machine for Ensuring Proper Mitosis.

Mitosis is a key step of eukaryote proliferation.Endosomal sorting complex required for transport, a protein complex closely associated with membrane shearing, is involved in endosome maturation, virus budding, and autophagy.The structural and functional abnormalities of the complex are associated with the occurrence and progression of cancer and other diseases.In this paper, we summarized the roles of the endosomal sorting complex required for transport in different stages of mitosis and reviewed the studies about the role of the complex in regulating mitosis in diseases.

Transcriptional activation of S100A2 expression by HIF-1α via binding to the hypomethylated hypoxia response elements in HCC cells.

Hepatocellular carcinoma (HCC) is one of the most prevalent and lethal cancers. Dysregulation of S100A2 has recently been found in many cancers including HCC. However, its regulatory mechanism in HCC remains poorly understood, especially in hypoxia. In this study, we found that S100A2 is upregulated and correlated with the clinicopathological features of HCC patients. Moreover, the elevated S100A2 showed worse overall survival. Functionally, S100A2 inhibition decreased the proliferation and migration of HepG2 cells. Interestingly, we found that HIF-1α directly binds to hypoxia response elements (HREs) of the S100A2 promoter region. S100A2 expression could be induced in an HIF-1α-dependent manner under hypoxia. Furthermore, S100A2 silencing significantly suppressed HCC cell proliferation and invasion under hypoxia. Mechanistically, pyrosequencing results showed that the hypomethylation status of CpG located in the HRE at the S100A2 promoter was correlated with S100A2 induction. Additionally, HIF-1α- mediated S100A2 activation was associated with TET2-related epigenetic inactivation. TET2 was enriched in the HRE of the S100A2 promoter in HepG2 cells. Finally, S100A2 methylation-related genes and pathways were analyzed. We found that the methylation of S100A2 is correlated with ANXA2, PPP1R15A, and FOS, which include in a hypoxia-related gene set from the GSEA database. Moreover, some EMT-related genes are associated with the methylation of S100A2 in HCC. Conclusively, our study thus uncovered a novel mechanism showing that hypoxia/HIF-1α signaling associated with DNA methylation enhances S100A2 expression in HCC. S100A2 may be useful as a target for facilitating novel diagnostic and therapeutic strategies in liver cancer.

BMP2 as a promising anticancer approach: functions and molecular mechanisms.

Bone morphogenetic protein 2 (BMP2), a pluripotent factor, is a member of the transforming growth factor-beta (TGF-ß) superfamily and is implicated in embryonic development and postnatal homeostasis in tissues and organs. Experimental research in the contexts of physiology and pathology has indicated that BMP2 can induce macrophages to differentiate into osteoclasts and accelerate the osteolytic mechanism, aggravating cancer cell bone metastasis. Emerging studies have stressed the potent regulatory effect of BMP2 in cancer cell differentiation, proliferation, survival, and apoptosis. Complicated signaling networks involving multiple regulatory proteins imply the significant biological functions of BMP2 in cancer. In this review, we comprehensively summarized and discussed the current evidence related to the modulation of BMP2 in tumorigenesis and development, including evidence related to the roles and molecular mechanisms of BMP2 in regulating cancer stem cells (CSCs), epithelial-mesenchymal transition (EMT), cancer angiogenesis and the tumor microenvironment (TME). All these findings suggest that BMP2 may be an effective therapeutic target for cancer and a new marker for assessing treatment efficacy.

NLRP3 Inflammasome Activation Enhances ADK Expression to Accelerate Epilepsy in Mice.

Epilepsy (SE) is a common and serious neurological disease. NOD-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome participates in the pathogenesis of SE, while its underlying mechanism is still unclear. Here, we attempted to explore the mechanism of action of NLRP3 inflammasome in SE. SE mouse model was constructed by administration of kainic acid (KA). Astrocytes were treated with KA to mimic SE cell model. MCC950 (NLRP3 inhibitor) and Z-YVAD-FMK (Caspase-1 inhibitor) were used to treat astrocytes to inhibit the activity of NLRP3 and Caspase-1. Nissl staining was performed to examine the morphology of neuron. Western blot, enzyme-linked immunosorbent assay and immunofluorescence staining were performed to assess protein expression. SE mouse model exhibited an increase of neuronal loss, and an up-regulation of Cleaved-Caspase-1, IL-1ß and IL-18 in hippocampus. The levels of GFAP+ADK+ cells were significantly increased in SE mice. MCC950 or Z-YVAD-FMK abolished these impacts conferred by KA in SE mice. Moreover, KA treatment enhanced the expression of NLRP3, Cleaved-Caspase-1, IL-1ß and IL-18 in astrocytes, which was rescued by knockdown of NLRP3 or Caspase-1. Additionally, CREB, p-CREB, REST were up-regulated, and SP1 was down-regulated in the KA-treated SE mice and KA-treated astrocytes. Inhibition of NLRP3 or Caspase-1 rescued these proteins expression in KA-treated astrocytes. CREB or REST silencing reduced adenosine kinase (ADK) expression, while SP1 knockdown enhanced ADK expression in KA-treated astrocytes. In conclusion, NLRP3 inflammasome activation enhances ADK expression to accelerate SE in mice through regulating CREB/REST/SP1 signaling pathway. Thus, inhibition of NLRP3 inflammasome may be a treatment for SE.